NGD and cognitive disorders

Question 1

NGDS

i) what are they? what must be excluded for dx?
ii) are inborn errors of metbolism classed as NGDs?
iii) name three core NGDs? what links these core diseases?

Answer 1

i) gradually progressive death of neurons in the CNS
- exclude other pathophysiology eg infective, inflammatory, vascular

ii) no
iii) alzheimers, parkinsons disease, dementia with lewy bodies, motor neurone disease

Question 2

PATHOPHYSIOLOGY OF NGDS

i) what happens to a normal protein? how does this lead to the formation of inclusion bodies?
ii) in relation to the protein - what causes symptoms of the disease? what ultimately happens to the neuron?
iii) what is the function of tau? what disease does it aggregate in?
iv) where is alpha synuclein found? what does it aggregate in?
v) what is the function of TDP-43 protein? which disease does it aggregate in?

Answer 2

i) normal protein > abnormal form eg misfolding or hyperphos
- protein aggregates into oligomers > inclusion bodies

ii) protein normal function is los and some can be toxic > symptoms
- neuron is lost and dies

iii) tau - normally stabilises MTs > agg in alz
iv) alpha synuclein - found throughout neurons, unclear func > agg in PD
v) TDP43 nuclear protein that binds DNA and RNA > agg in MND

Question 3

PATHOLOGY AND CLINICAL FEATURES OF NGDs

i) name five domains that cognitive symptoms can occur in?
ii) what impairment does AD cause? what happens later?
iii) what does MND cause? what happens later? (2)
iv) name three things that are used to differentiate between NGDs

Answer 3

i) memory, executive (memory, organising, multi tasking), language, visospatial, social behav, psyc (low mood, anx, paranoid, hallucinations)
ii) AD > cognitive impir and later movement disorder
iii) MND > weakness > behavioural/aphasia later
iv) use clinical syndrome (history, exam, cog test), imaging (MRI, PET, DAT), CSF markers (ab, tau protein)

Question 4

ALZHEIMERS DISEASE

i) which two proteins are implicated? which one is found extracellular?
ii) which area do these proteins also accumulate outside the brain?
iii) which protein appears first? which one correlates with cognitive deficits
iv) what symptom is usually seen first? name three late features

Answer 4

i) neuronal inclusions/NF tangles containing tau
- beta amyloid containing ab protein > extracellular

ii) amyloid also collects in walls of arterioles

iii) amyloid appears first
- tau location correlates with cognitive deficits

iv) usually see memory symptoms first
- late features > parkinsonism, myoclonus, spasicity

Question 5

ALZHEIMERS DISEASE RF AND TREATMENT

i) which genetic polymorphism is the most common? which allele has the highest risk?
ii) name two dominantly inherited single genes that rarely cause AD? when do these sually have onset?
iii) what does stronger congitive reserve correlate with in terms of dx? how do vascular RF affect AD symptoms?
iv) name two treatments that may boost cognitive function? name two drugs that can make it worse

Answer 5

i) apolipoprotein E > three alleles, E4 has highest risk
ii) PSEN1, PSEN2, APP > onset in early-mid adulthhood

iii) stronger cog function > later dx
- vascular RFs worsen AD symptoms

iv) ACEi and memantine can boost cog function
- anti muscarinics and anti psychotics can make it worse